Corticotropin releasing factor (CRF), a 41 residue peptide, coordinates the endocrine, behavioral and autonomic responses to stress. Data from studies of cerebrospinal fluid, postmortem tissue receptor measurements and CRF stimulation tests support the hypothesis that CRF is hypersecreted in depressed patients. There is also evidence for an involvement of CRF in the pathophysiology of anxiety disorders. In addition, peptide CRF-receptor antagonists show efficacy as anxiolytics in a variety of animal models. Therefore, agents that antagonize the CRF receptor may prove useful in treating depression and anxiety without many of the limiting side effects of existing therapies. In Phase I studies, four patentable series of small molecule non-peptide CRF receptor antagonists (M.W. <500) have been identified through a combination of high throughput screening, drug design, molecular modeling and solution phase combinatorial chemistry. Several potent CRF receptor antagonists (Ki equal to or more than 10 nM) with anxiolytic effects in rodent models of anxiety have been synthesized and one compound has been identified as a Lead compound. The major goal of the current proposal is to identify orally active, high affinity CRF receptor antagonists with optimal anxiolytic/antidepressant properties and without limiting side effects. This will be accomplished through a combination of rational drug design and solution phase automated combinatorial chemistry to optimize our proprietary molecules for in vitro activity and selectivity at the CRF receptor and in vivo activity in a variety of animal models of anxiety and depression. In parallel, studies will be carried out to validate additional in vivo assays for anxiety and depression and to develop ex vivo and in vivo methodologies with radiolabeled high-affinity small molecule CRF receptor antagonists for correlating receptor occupancy with the pharmacological effects of potential development candidates.